Gene therapy shows new signs of promise

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Alan Smith can still recall his excitement, in the early 1990s, over early experiments in lab rats that demonstrated gene therapy’s potential power to attack diseases such as cystic fibrosis.

Smith, a former chief scientific officer at Genzyme, the Cambridge biotech company, remembers feeling like the experiments were “steppingstones” to developing a whole new wave of medicines for untreatable diseases. Often, they were touted in Genzyme’s annual reports, and the research was funded with tens of millions of dollars from stock market investors.

But more than two decades later, there is still no gene therapy that has won approval from the US Food and Drug Administration, and Genzyme gave up on it as a potential approach to treating cystic fibrosis. What seemed in the 1990s to be a new world just over the horizon kept receding. There were years of “slow, quiet progress,” in Smith’s words, but also setbacks, including deaths and complications for patients who enrolled in early trials.

In 2013, though, there are signs that patients might soon start benefiting from gene therapies. A Cambridge company, Bluebird Bio, last month filed to sell stock to the public; it hopes to raise $86 million to bring to market a gene therapy that would treat a rare, fatal neurodegenerative disease known as CCALD. (Bluebird’s roots go back to 1992, when it was founded as Genetix Pharmaceuticals.)

A Dutch company, uniQure BV, is working to set up a production facility in the Boston area that could eventually employ 50 or more people, according to Philip Astley-Sparke, president of uniQure’s new US division. In November, the company received regulatory approval in Europe for a gene therapy called Glybera, which treats patients with a rare metabolic disorder that causes inflammation of the pancreas. It’s the first gene therapy to receive regulatory approval anywhere in the Western world — though not yet from the FDA.

How exactly do these new therapies work? Instead of a pill or an injection to treat a chronic ailment, many of the gene therapy approaches essentially try to install a microscopic factory inside your body. Its job is to crank out a missing enzyme or therapeutic protein continually, over the course of years. Studies in primates have seen these factories operate for more than a decade.

The factories themselves are created by using disarmed viruses — the same ones that might ordinarily give you the flu — that have been packed with custom-crafted DNA or RNA. They infiltrate cells in your body and tell them exactly what to make. (The use of viruses for good, not evil, dates back to the late 1700s, when scientists discovered how to inoculate people against smallpox.) These viruses can be delivered to the body by injection or inhalation, or by removing cells from the patient, exposing them to the virus, and reintroducing them to the patient.

Bluebird takes that last approach with a product it is developing for childhood cerebral adrenoleukodystrophy, a disease that affects boys between the ages of 4 and 10, usually leading to a vegetative state and death. (It was featured in the movie “Lorenzo’s Oil.”) UniQure’s product, Glybera, is delivered via a one-time set of injections to the leg. In this case, the factory is making a protein that helps the body break down fats. Without it, the pancreas becomes inflamed, which is painful and in some cases fatal.

Somewhere between 1,000 and 5,000 people in the world have the disease Glybera targets, called lipoprotein lipase deficiency. Given that small patient population, uniQure’s treatment will set a record for drug prices: about $1.6 million per patient. It is expected to be on the market this year. But uniQure’s local facility probably won’t produce Glybera, according to Astley-Sparke. It will make future gene therapy products for the company, targeting diseases like hemophilia. “We hope to have it up and running around 2015,” he says.

Other companies are focusing on diseases that affect larger patient populations.

Genzyme, now a part of the French pharmaceutical giant Sanofi SA, never abandoned its research into gene therapy. Sam Wadsworth, head of gene therapy research and development, arrived at the company in 1993. Since then, “we have been consistently and persistently and stubbornly pursuing this,” he says.

The company is working on a treatment for age-related macular degeneration, a common cause of blindness in people over 50, and for Parkinson’s, a neurodegenerative disease. Between 7 million and 10 million people worldwide suffer from Parkinson’s according to the Parkinson’s Disease Foundation, a patient advocacy group.

In Parkinson’s, Wadsworth says, there is already evidence that the gene treatment may have an effect for as long as five years, helping supply an enzyme lacking in those who have Parkinson’s and allowing them to stay on lower doses of a drug they use called Levodopa. In macular degeneration, Genzyme’s clinical trial is still recruiting patients; some will be treated locally, at Ophthalmic Consultants of Boston.

A Tufts University School of Medicine spin-out, Hemera Biosciences, raised $3.75 million earlier this year, an amount it hopes to use to start clinical trials of a gene therapy treatment for age-related macular degeneration.

In March, the investment bank Lazard Capital Markets published a research report optimistically titled “Gene Therapy: The Time is Now.” It cited uniQure’s approval in Europe as a major turning point for the approach. And last fall, Smith attended a meeting of investors at the Royal Society in London, where the consensus was that gene therapy, more than 20 years after his early research at Genzyme, is now a promising place to deploy capital.

“I remain excited,” says Smith, now semiretired and living in Wayland. “Eventually, this will crack. There’s no doubt.”

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